Conversations With Prostate Cancer Experts

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Dr. Paul Cathcart is a consultant urological surgeon at Guy’s Hospital and St. Thomas’ Hospital in London.

Prostatepedia spoke with him about a clinical trial he’s running that looks at robotic surgery in men whose prostate cancers have come back after focal therapy.

Why did you become a doctor?

Dr. Paul Cathcart: I always liked science; that was my favorite subject. I was thinking about whether to become a vet or a doctor and did lots of school visits. During one of those visits, I met an inspirational character, a surgeon. I spent some time with him, following him around hospital wards and clinics. I thought that he was the sort of person I would like to be: he does the job I’d like to do. I think that’s often the case in life: you meet some inspirational figure who pushes you along one line.

Later on, another inspirational figure who came into my life was a urologist. I was originally going to be a colorectal surgeon. Everything was set for that. Then I met this urologist who showed me the different mix there is in urology, which I found interesting. Then I met Dr. Mark Emberton; I was his research fellow for many years. He’s quite an inspirational person as well. I’ve been working with him for 17 years now on various things.

What is the thinking behind your trial on robotic surgery after focal ablation?

Dr. Cathcart: Focal therapy is a new concept, which Dr. Emberton and one or two other people have pioneered to reduce the side effects and morbidity of prostate cancer treatment. Unfortunately, a proportion of these patients will experience recurrent disease after focal therapy. No cancer treatment is 100% effective. A couple of these focal therapy patients were recurring three or four years after starting the focal therapy program.

No urologist wanted to operate on these patients because they felt that it would be an extremely difficult surgery. In fact, urologists were only offering exenterations to remove the patients’ prostate, bladder, etc.

I got to know quite a few of these patients. (I do a lot of post-radiotherapy surgery, as well.) I decided that this procedure called salvage surgery interested me. We thought that we could do this salvage surgery and maintain good outcomes for our patients because only part of their prostate had been treated during focal therapy. We thought that the side effects of the surgery after focal therapy would actually be a lot less than after radiation, but we needed evidence to prove it. That is why we set up the trial.

We’re also interested in learning why some patients may fail focal therapy. What is it about their disease that leads it to recur? If we can understand why some patients may fail focal therapy, this can help us select up front which patients should have focal therapy and which should not.

What can patients expect to happen during the trial?

Dr. Cathcart: We are halfway through the study at the moment.

Of course, patients undergo a salvage prostatectomy. We take the tissue to be analyzed and look for various genetic markers to see why their cancer may have returned.

This is also a toxicity and side effect study. We have patient-reported outcome measures at baseline and sequentially thereafter. There are a number of blood tests looking at hormone profiles before and after the surgery.

We follow patients for about 12 months after those sequential patient-reported outcome measures; we’re looking to chart that toxicity.

I’ve taken out more prostates after focal therapy than most because of my link with Dr. Emberton. We’re now demonstrating the feasibility and toxicity of salvage focal surgery and trying to understand why these tumors have recurred.

Are you still recruiting patients?

Dr. Cathcart: About 20 patients have undergone the surgery. We’re recruiting 20 more. We haven’t had any adverse events. We were worried about things like rectal injuries, because the rectum can stick to the prostate after focal therapy. We haven’t had any of those.

We’ve actually had a fantastic continence outcome. The prostate cancer community said everyone would be incontinent and impotent, but all our patients so far have been continent.

We’ve got the patient-reported outcome measures to demonstrate it.

The potency rates are taking a little bit longer to return to baseline. The outcomes from potency won’t be as good as the continence outcomes. We haven’t had any side effects at the time of surgery. No complications or anything, so we’re delighted with the way things have gone.

Does the fact that the man has had focal therapy make the potency issues worse?

Dr. Cathcart: It depends on the location of their focal treatment. In those with anterior tumors (tumors away from the neurovascular bundles), we’ve noticed potency returns faster. If they’ve had an ablation on the peripheral zone, near where one of the nerve bundles is located, potency returns more slowly.

We’re also noticing a difference between different treatments. You can give focal therapy with high-intensity focused ultrasound (HIFU), cryotherapy, or something called electroporation. The different energy sources have different effects on the structures surrounding the prostate and a different impact on the chance of potency returning. Electroporation seems to be very precise and leaves the least amount of collateral damage. In those patients, potency returns faster. Cryotherapy creates more periprostatic fibrosis and scarring; potency takes slightly longer for those patients to return. Potency return for HIFU patients falls somewhere in the middle of the modalities.

I’ve also taken out prostates after photodynamic therapy. Photodynamic therapy is better relative to preserving the tissue planes, but it does depend on which part of the prostate has been ablated in the first place.

Is there anything else you think patients should know about your trial?

Dr. Cathcart: We’re going to get a great understanding of why these patients in particular failed focal therapy. The genetic markers and the locations of the tumors will inform which patients are suitable for focal therapy from the beginning. There may be parts of the prostate, or particular types of tumors or genetic markers, which will identify patients best suited to a whole-gland approach such as a radical prostatectomy up front.

It’s not just about the location and grade of the tumor, but also about the tumor’s genetic signature, which may predispose a particular tumor to being better suited for focal therapy.

It’s interesting, in some patients you knock out one tumor say on the right-hand side and that’s it, the tumor never comes back. Other patients’ prostates seem somewhat unstable and have multiple tumors that keep appearing throughout the prostate. I’m sure there is a genetic basis to it.

Because we’re taking out these patients’ prostates, we can analyze all the different tumors. Some people even think that by treating part of the prostate we may be changing the genetics of that tumor—i.e., it gets angrier. I don’t think that’s the case. This study will help prove that point. We’re also going to open up a comparative arm of the study very soon for patients who have had whole-gland radiation or ablation techniques—open to anyone who has had the whole of their prostate treated with brachytherapy, radiotherapy, HIFU, or cryotherapy. We’ve been finding that patients who have had surgery following focal therapy have better outcomes than those who have had whole-gland therapy up front. We’re going to recruit into that second arm to demonstrate that surgery after focal therapy has a better outcome.

Can non-UK residents come to you for surgery?

I’ve got a clinic called the Recurrent Prostate Cancer Clinic. I have a reasonable number of patients who come from the United States. They normally come to Dr. Emberton for focal therapy, then if they develop recurrent disease, I operate on them. A lot of urologists wouldn’t operate on these patients. Certainly, in the United States, hardly anyone operates on post HIFU patients simply because HIFU has not been available until very recently.

How did focal therapy even become in vogue? To abate some of the potential side effects of whole-gland treatment. It is exciting and promising, yet remains investigational.

Isn’t a focal approach common in other kinds of cancers?

Dr. Karnes: It can be. The most common is probably breast cancer. I’m far from an expert in breast cancer, but recurrence rates can be higher with focal therapy, meaning a lumpectomy or quadrantectomy, where a quadrant of the breast is removed. But, the survival has been similar between partial- vs. whole-breast treatment.

Why not the prostate? I would say that focal therapy, in general, hasn’t risen to the forefront in the United States or internationally. There are a couple of limitations for focal therapy in general:

1) What do we know about prostate imaging? Prostate cancer is known to be a multifocal cancer within the prostate. The multiparametric MRI is good. It’s not perfect. But even if we can identify a small focus of intermediate-grade prostate cancer, are we certain that is truly the disease to treat, as opposed to some scattered higher-grade cancer that may not be showing up on MRI, but hopefully might get picked up on a whole-gland biopsy done along with a targeted biopsy? I think we’re getting to the point where an MRI is pretty good at imaging the entire prostate.

2) We still have a second unresolved issue of what constitutes the biological index lesion of the cancer. If we do have multifocality, are we sure exactly which focus to treat? Even some of the well-known researchers in focal therapy (focal cryotherapy, high-intensity focused ultrasound [HIFU]) can still have patients with a fairly high recurrence, or persistence of the cancer after the partial or focal therapy about 20% of the time.

What is salvage focal therapy?

Dr. Karnes: Focal salvage therapy is focal therapy done when a man recurs after primary treatment. There is more at risk with focal salvage therapy. What do I mean by more at risk? Obviously, salvage therapy means that there has already been a primary treatment that has failed, so there is even more impetus to get it right the second time around. For that second time around, if we go back to those two items that I mentioned above (imaging and the biology of the index lesion), there has not been, to my mind, enough research into MRI imaging of recurrent prostate cancer. More research needs to be done into the MRI performance accuracy after a radiation.

Dr. Mark Emberton is a Professor of Interventional Oncology at University College London.

Prostatepedia spoke with him about focal therapy for prostate cancer.

What is focal therapy for prostate cancer?

Dr. Emberton: Focal therapy is an attempt to improve the therapeutic ratio. It addresses the harms and benefits of treatment. In prostate cancer treatment, the harms are too great for the benefit to accrue.

We can’t improve the benefit very much, but we can certainly reduce the harms that we inflict on our patients. Nearly every patient who has been treated for prostate cancer will experience a reduction in quality of life because of the impact on his sexual function, continence, or rectal function.

Focal therapy attempts to address that by preserving tissue. We’ve managed to preserve tissue in all other cancer management: breast through lumpectomy, kidney through partial nephrectomy, liver through partial hepatectomy, and penile cancer through partial penectomy. Prostate is the last bastion. Until recently, all men had the prostatic equivalent of bilateral mastectomy. In other words, their whole prostate tissue was removed irrespective of tumor volume, location, or number. Everyone was treated the same. With focal therapy, we attempt to preserve tissue, which preserves function.

How do doctors determine if focal therapy is appropriate for a man?

Dr. Emberton: It’s not for everybody. At the moment, we do surveillance so that men with very low-risk disease have no treatment. We offer surgery to men with high-risk disease who’ve got extensive, high-burden tumors in the same way we manage, say, breast cancer. We might choose to watch an elderly woman with a small breast lump. We might choose to do a mastectomy on a young woman with very aggressive breast cancer. But the majority of women—currently 80%—can get away with a lumpectomy. This is enabled by the ability to identify tumors and determine location and volume.

That’s a very recent development in prostate cancer. Until very recently, we were treating all men blindly. Since Hugh Hampton Young did his first prostatectomy at Johns Hopkins about 100 years ago, we’ve been treating prostate cancer without knowledge of tumor location.

What is the role of imaging?

Dr. Emberton: The new trick in town is that we can see the prostate cancer with MRI. If we can see it, we can direct needles at it. If we can direct needles at it, we can direct energy at it. We can zap the tumor rather than having to remove the whole prostate. We can have a much more nuanced approach now. Instead of treating all men the same, we can now stratify men by risk with great precision by biopsying them differently depending on where the tumor is and then allocating treatment depending on the risk stratification that has been assessed. If a man has one millimeter of Gleason 4+3, most of us would not treat. I certainly wouldn’t. If he has extensive bilateral disease, I would offer whole-gland treatment in the form of surgery or radiation therapy. If he has got a 0.5 cc tumor in the right peripheral zone of the prostate, I see no reason why we shouldn’t offer a selective destruction of that tumor that preserves erections, ejaculation, and continence. We’re doing that today. We’re having conversations with men today that we couldn’t have had three to four years ago because we didn’t have the tools.

What about other advances in imaging?

Dr. Emberton: PSMA is very useful in staging men. It’s concordant with MRI and the prostate, but it doesn’t give us the spatial resolution that we would require to decide which part of the prostate to treat. The PSMA PET/CT will be positive on the left or the right side of the prostate, but will not give us any more information. It’s really useful in the high-risk man with whom you’re trying to rule out metastatic disease.

There are a variety of forms of focal therapy, correct?

Dr. Emberton: I think conceptually, it’s very clear. We offer men focal therapy when we can treat the tumor plus a margin and we think we can do so faithfully. But there are lots of ways to do it. Just like surgery, you can have an open, transperineal, laparoscopic, or robotic prostatectomy. In brachytherapy, high-dose rate (HDR), low-dose rate (LDR), CyberKnife, TrueBeam, protons, external beam, the principle is the same.

Yes, we have a few options with focal therapy, though not as many as surgeons and radiation therapists. We’re often accused of having a cornucopia of ways of treating. Actually, we don’t. We have heat (hot or cold) and we have electricity in the form of radio frequency or electroporation.

David Crawford, the distinguished Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology, at the University of Colorado Anschutz Medical Campus frames Prostatepedia’s November discussions on focal therapy for prostate cancer.

There is a lot of interest in focal therapy right now. Years ago, when I used to recommend radical prostatectomy and radiation to patients, they would ask why I couldn’t just take out a part of their prostate and not the whole thing. I would chuckle and say, “You can’t do that.” I’d say that prostate cancers tend to be multifocal. We can’t just operate on part of your prostate. We have to treat the whole thing.

That resonated with many urologists for years. Then Drs. Gary Onik and Winston Barzell started using cryotherapy to ablate prostate tumors and mapping biopsies to localize the cancer. Like a lot of things in medicine, there was a backlash of people who felt focal therapy was inappropriate because prostate cancer is multifocal.

Dr. Onik persisted. When somebody came in with a low-grade or even intermediate-grade prostate cancer on the left side of the prostate gland, he would biopsy the right side of the prostate extensively. If there wasn’t any cancer, he would do an ablation and treat the whole left side. That was the beginning of focal therapy.

I became interested in what I call targeted focal therapy about 15 years ago. Of course, focal therapy hinges on our ability to effectively biopsy patients so that you know you’re not missing other, more aggressive tumors. Focal therapy means focally treating a lesion, but I like the term targeted focal therapy because we’re targeting exactly where the tumor is with our mapping biopsies.

There are many ways to do focal therapy. We can use lasers, cryotherapy, or high-intensity focused ultrasound (HIFU). We’re working on using immunotherapy to target lesions. We can even put alcohol into the lesion and get rid of the cancer that way. Ablating the tumor isn’t the hard part. The hard part is knowing where the lesion is and targeting it.

Fifteen years ago, we had several hundred radical prostatectomy specimens; a researcher from Japan named Dasako Hirano, who had been with us for two years, outlined the tumors on acetate paper and then we put them into a 3D system so that we could simulate where these tumors were using different biopsying techniques. We showed that if you use the transperineal approach to place a needle into the prostate every five millimeters, you could sample the whole prostate without missing many significant cancers. I felt that it was safe to go forward with targeted focal therapy.

We knew we would not do any harm with 3D mapping biopsies.

We also talk about MRI in relation to focal therapy. MRI has been around for a long time. We’ve gone from 1 Tesla to 3 Tesla and now 5 Tesla MRI units. We’re getting better at reading the MRI results. There has been a lot of discussion about how accurate MRI is and what it misses. MRIs still can miss aggressive cancers. Depending on which expert you believe, MRI misses anywhere from 7-10% up to 30% of aggressive cancers. MRI is a lot simpler than our painstaking 3D mapping biopsy, though, so it’s caught on.

Dr. Mark Emberton was the first to champion MRI in the United Kingdom. Dr. Emberton and his team now have a lot of experience in using MRI in focal therapy, primarily cryotherapy.

But to me, the gold standard remains the mapping biopsies. MRI is good, but not perfect. Perhaps we can use molecular markers along with MRI to rule out more aggressive cancers.

Focal therapy is a response to overtreatment and it does have a place, but with prostate cancer, we’ve got to follow people a long time before we come to a consensus.

Last month we reviewed the impact of new tools like imaging on treatment choices for newly diagnosed men. We discussed how improved imaging impacts planning of both radiation therapy and surgery, as well as the role imaging plays in active surveillance in terms of patient selection and monitoring. .

This issue is a logical extension of those conversations as we look at focal therapy treatment options based on those imaging tools. The renaissance of focal therapy is due to MRI, which has the ability to visualize cancer within the prostate gland with much greater precision than older techniques.

Focal treatment makes sense when the cancer is of limited extent, usually limited to a single major lesion on one side of the prostate. If the cancer is truly limited to only part of the gland, it may not be necessary to destroy the whole prostate. The hope is that focal therapy will have less impact on sexual function and urination than radical prostatectomy or radiation therapy to the whole gland. A frequently used analogy is a lumpectomy versus mastectomy for breast cancer.

As you read the interviews, there are a number of issues to keep in mind. With radical prostatectomy and radiation therapy, we know in detail the odds of long-term cancer control. This information is lacking for the various forms of focal therapy. One reason that cancer control might be less complete after focal therapy is that focal therapies largely depend on the ability of the MRI to identify patients with cancer limited to one area of the prostate gland. But, as we learned last month, the MRI is not a perfect tool and can miss small, aggressive cancers. Also, first-rate MRI facilities with well-trained radiologists are limited in number.

As a medical oncologist, I have recently had to deal with a particularly difficult situation. With the arrival of new, highly sensitive imaging for metastatic disease, such as the C-11 Acetate, fluciclovine F 18, and PSMA PET/CT scans, I am seeing a growing number of patients who have had radiation therapy and the only detectable recurrent cancer is in the prostate gland. Focal therapy in this setting is difficult because of radiation damage to surrounding normal tissue as well as dense scar formation within the gland. Several interviews touch on treatment options for this situation, but those options are far from ideal. It is unclear what the right path is for these men.